Abstract
Poly(ADP-ribosyl)ation is a post-translational modification of various proteins and participates in the regulation of chromatin structure and transcription through complex mechanisms not completely understood. We have previously shown that PARP-1, the major family member of poly(ADP-ribose)polymerases, plays an important role in the cell cycle reactivation of resting cells by regulating the expression of Immediate Early Response Genes, such as c-MYC, c-FOS, JUNB and EGR-1. In the present work we have investigated the molecular mechanisms by which the enzyme induces c-MYC transcription upon serum stimulation of quiescent cells. We show that PARP-1 is constitutively associated in vivo to a c-MYC promoter region recognized as biologically relevant for the transcriptional regulation of the gene. Moreover, we report that serum stimulation causes the prompt accumulation of ADP-ribose polymers on the same region and that this modification is required for chromatin decondensation and for the exchange of negative for positive transcriptional regulators. Finally we provide evidence that the inhibition of PARP activity along with serum stimulation impairs c-MYC induction by preventing the proper accumulation of histone H3 phosphoacetylation, a specific chromatin mark for the activation of Immediate Early Response Genes. These findings not only suggest a novel strategy by which PARP-1 regulates the transcriptional activity of promoters but also provide new information about the complex regulation of c-MYC expression, a critical determinant of the transition from quiescence to proliferation.
Highlights
Poly(ADP-ribose)polymerases, termed ADP-ribosyltransferases with diphtheria toxin homology (ARTDs) according to a new nomenclature [1], catalyze the polymerization of ADP-ribose units from NAD+ on acceptor proteins, leading to the formation of linear or branched polymers of ADP-ribose
By means of PARP inhibition and PARP-1 knock-down, that the enzyme activation is required for resting cells to emerge from quiescence
In the present work we have focused on the role of poly(ADPribosyl)ation in the induction of c-MYC transcription and, in particular on the functional interaction of PARP-1 with c-MYC promoter
Summary
Poly(ADP-ribose)polymerases, termed ADP-ribosyltransferases with diphtheria toxin homology (ARTDs) according to a new nomenclature [1], catalyze the polymerization of ADP-ribose units from NAD+ on acceptor proteins, leading to the formation of linear or branched polymers of ADP-ribose. Poly(ADP-ribosyl)ation has been implicated in several distinct processes regulating chromatin structure and transcriptional activity, both at global and gene-specific levels [2]. Genome-wide analysis of PARP-1 binding in tumor cells showed that the protein localizes to the promoters of almost all actively transcribed genes [4], which suggests that it plays a role in promoting the formation of chromatin structures that are permissive to transcriptional activity. Its binding to a wide range of DNA sequences or to specific structures can change the activity of enhancers and promoters [2]. PARP-1 binding to nucleosomes can promote, through histone poly(ADPribosyl)ation, the relaxation of the chromatin structure and the reorganization or repositioning of the nucleosomes [5,6]
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